Asthma begins in early life, and is linked to immune dysfunction that skews responses towards allergy. Human epidemiology identifies 'prenatal programming'for asthma susceptibility through the risk factor of maternal asthma. Our pilot data in maternal allergy reveal that the neonatal dendritic cell (DC) is the critical cellular agent of asthma susceptibility, since adoptive transfer of DCs from asthma- susceptible juvenile mice causes new asthma risk in otherwise normal pups. Genome-wide analysis of DNA methylation shows substantial differences in 'asthma-susceptible'DCs compared to controls. In addition to maternal asthma, other environmental exposures (e.g. tobacco smoke, air pollution) cause neonatal asthma risk, but mechanisms remain poorly characterized. Our experimental studies in normal mother mice show that various 'environmental stressors'all result in babies that are more susceptible to developing allergic airway disease. Our central hypothesis is that multiple environmental stressors cause early life asthma susceptibility through epigenetic modifications in neonatal DCs, which confer pro-asthmatic skewing of immune responses. Specific Aims: Aim 1 will use adoptive transfer of DCs to test the postulate that multiple maternal exposures (air pollution, chemical dermatitis, stress) all produce an altered 'asthma-susceptible'DC, similar to that observed in offspring of mothers with OVA-induced allergic asthma. DC subpopulations will be further characterized to optimize epigenetic analyses. Aim 2 will use genome-wide and targeted epigenetic analysis to test the prediction that 'asthma-susceptible'DCs will share epigenetic marks linked to skewing towards a pro- asthmatic DC phenotype. Aim 3 will test the hypothesis that the shared mechanism for myriad maternal 'environmental stressors'is a transplacental stress hormone response which causes the epigenetic and functional changes seen in 'asthma-susceptible'neonatal DCs Impact &Significance: The planned studies will identify how multiple environmental exposures of pregnant mothers cause asthma risk, and will provide targets for public health and therapeutic interventions. PUBLIC HEALTH RELEVANCE: The planned studies will identify how multiple environmental exposures of pregnant mothers cause asthma risk, and will provide targets for public health and therapeutic interventions.